Research

Current Research Projects:

Dr. Afrin's clinical (and clinical research) interests include benign heatologic and mast cell disorders; he also has an extensive background in computer science and has been pursuing research and development in medical informatics since 1978. Dr. Afrin's research interests/specialties include:

Dr. Costa is actively involved in research pertaining to the development of new therapies for lymphoid malignancies and novel approaches to hematopoietic stem cell transplantation. He currently serves as PI of ten industry-sponsored research projects, as well as two federal grants. He has 41 and counting publicatoins in peer-reviewed journals such as Blood and Bone Marrow Transplant and the British Journal of Hematology.

Dr. Costa’s main interest is in the development of innovative therapeutic strategies in lymphoid malignancies. In addition to being the local PI in several non-Hodgkin lymphoma and multiple myeloma trials, Dr. Costa has launched an investigator-initiated trial using two new agents (lenalidomide and ofatumumab) for the management of relapsed chronic lymphocytic leukemia. This trial was designed with prospective assessment of biomarkers and will allow detailed understanding of the in vivo effect of these two compounds in the leukemia cells and in the immune system. Dr. Costa was recently appointed Director of Research for the Medical University of South Carolina’s (MUSC) Hematopoietic Stem Cell Transplantation (HSCT) Program. He is also interested in the development of strategies that will improve the safety and efficacy of HSCT. Dr. Costa developed and validated a new cost-based algorithm for autologous HSC mobilization with 100% mobilization success and 93% predictability. Working in collaboration with Dr. Robert Stuart, he has developed an investigator-initiated trial for reduced intensity allogeneic transplantation in advanced hematologic malignancies. This trial encompasses an innovative transplantation approach to advanced B cell malignancies, integrates radioimmunotherapy into the conditioning regimen, and incorporates an mTOR inhibitor as an enhancer of the cytotoxic effect of the conditioning regimen and anti graft-versushost disease (GVHD) prophylactic agent. Another area of interest for Dr. Costa is the development of biomarkers for GVHD. Collaboration has been established with Dr. John Arthur, director of the MUSC Nephrology Proteomics Facility, to discover and validate early biomarkers for severe acute GVHD based on plasma exosomes.

Harry Drabkin, M.D. and Robert Gemmill, Ph.D.

Discoveries of genetic alterations in lung and kidney cancers have provided the foundation for investigations carried out in our group. In lung cancers, our group discovered the SEMA3F gene and showed it was a potent tumor suppressor. Ongoing studies are examining its ability to block angiogenesis, and to develop approaches for use as a therapy. Loss of E-cadherin is another common event in lung cancers that is a critical step in metastasis. This loss is often mediated by transcriptional repressors like ZEB and SNAIL and our recent work has shown that ZEB inhibits SEMA3F. This apparent linkage between a tumor suppressor and a metastasis inducer is under active investigation. In kidney cancer, we discovered the TRC8 gene, which is a membrane-bound tumor suppressor with ubiquitin ligase activity disrupted in selected families with hereditary kidney cancer. We are actively searching for ubiquitylation targets, as this activity appears essential for growth suppression. TRC8 is regulated by sterols and it interacts with components of the lipid homeostatic machinery, and with a translation initiation factor. These data suggest that TRC8 provides a regulatory linkage between the lipid biosynthetic process, protein synthesis and growth control.

Basis Research: Transglutaminases: Structure and FunctionClinical Research : Diagnosis and Treatment of ThrombosisTranslational Research: Development of TGM-2 Inhibitors

Basic Science: Transglutaminase Structure and Function.Recombinant DNA and protein biochemistry techniques are used to study the structure and function of Factor XIII and tissue transglutaminase (TGM-2). Collaborative studies with the Structural Biochemistry Lab at MUSC are studying mechanism of action of recently identified TGM-2 inhibitors.

Clinical Research: Diagnosis and Treatment of Thrombosis.Earlier studies led to FDA approval of the D-dimer assay and PFA-100 instrument. Danapioid (Ong10172) a heparinoid was discovered to treat heparin-induced thrombocytopenia and thrombosis. The hep-PF4 assay identified patients at risk for poor clinical outcomes and new approaches to manage this disorder are being studied.. The D-dimer antigen was found to be a surrogate marker for vascular damage in sickle cell disease and studies are in progress to monitor the effect of antithrombotics in sickle cell disease. Clinical trials are in progress to test the safety and efficacy of newly approved antithrobotic drugs for prevent of deep vein thrombosis. New instrumentation that uses whole blood is being studied as an improvement in evaluating bleeding risk of liver disease patients in collaboration with MUSC Liver Center and Pathology Departments.

Translational Research: Development of TGM-2 Inhibitors.Coagulation, inflammation and fibrosis are often associated with human disease processes. The lab is developing inhibitors to TGM-2 and examining their effect on fibrosis and inflammation. TGM-2 inhibitors were recently discovered to be effective therapy for the neurodegenerative process using Drosophila. The effect of these agents in other neurodegenerative diseases is also being studied in collaboration with the MUSC Neurosciences.

We continue to study the control of apoptosis in tumor cells using the Bcl2 antagonist ABT737. This agent is currently under study in the clinic for treatment of lymphoid malignancies and small cell lung cancer. We are studying the ability of this agent to induce senescence rather than apoptosis, and find that this is cell line specific. Additional biochemical experiments are being carried out to understand how this agent works.

The second project under study in the laboratory is the role of the Pim protein kinase in malignancy. To study this enzyme, we have developed specific small molecule inhibitors of Pim and investigated their activity against tumors. In the study of hematopoietic malignancies we find that these inhibitors are most active against T-cell ALL while they have growth inhibitory activity against myeloid leukemias, as well. Further evaluation of these agents as antileukemia treatments is continuing.

We have also investigated the role of Pim in regulating tumor growth through modulation of the mTOR pathway. By using Pim knockout fibroblasts we find that the absence of Pim markedly decreases the mTOR pathway activity. We find an increase in AMPK phosphorylation and a decrease in raptor protein to account for this change. This inhibition of the pathway is paralleled by an increase in the AMP/ATP ratio that is responsible for stimulating AMPK.

Additional experiments are underway to look at the role of Pim during normal stem cell development and the ability of this protein kinase to regulate prostate tumor growth. These studies are taking place using animal models and tissue culture experiments.

Michael Lilly, M.D.

Dr. Lilly’s research efforts are focused on ways to improve the care of patients with advanced prostate cancer. Cancer treatments often induce survival responses in cancer cells, resulting in limited efficacy. These survival responses are mediated in part by PIM kinases, enzymes that regulate cancer cells’ survival machinery. Current studies are looking at the biochemical events that are regulated by PIM1 kinase, using both experimental and bioinformatics approaches. These studies suggest that PIM1 regulates a network of other kinases which coordinate expression of multiple survival genes. His group is also studying mutations in the PIM1 kinase that occur in cancer patients. These mutant enzymes show unique patterns of sensitivity to known PIM1 kinase inhibitors that may be relevant to the choice of cancer treatments. In addition to laboratory studies, Dr. Lilly also conducts clinical trials in patients with advanced prostate cancer. His primary interest is in investigator-initiated, early phase clinical trials. A recent trial studied the use of dasatinib, an oral medicine that inhibits kinases (growth promoting enzymes) in cancer cells. This study documented that dasatinib has activity against advanced prostate cancer, possibly by inhibiting the expression of a tumor growth factor called IL-6.Current studies combine standard chemotherapy drugs with nutritional supplements or with antibodies that destroy tumor blood vessels. Treatment of younger patients with aggressive prostate cancer is a particular interest for Dr. Lilly. His clinical studies examine the potential benefits of chemotherapy treatment given immediately after surgery for young, high-risk prostate cancer patients. Dr. Lilly’s studies have been supported by grants from the National Institutes of Health, the Department of Defense, and numerous pharmaceutical companies.

Dr. Stuart's research interests center on the pathogenesis and treatment of hematological malignancies. He is currently the Medical Director of the Clinical Trials Office and has served as the Principal Investigator of mutliple clinical trials.